Dermatomyositis (DM) is a rare and debilitating, systemic, autoimmune disease. While heterogenous in presentation and severity, DM is primarily characterised by a spectrum of skin and muscle disease, which may include proximal muscle weakness and recalcitrant cutaneous eruptions. DM may also be associated with joint pain and stiffness, inflammatory arthritis, dysphagia, fatigue, and calcinosis. The current standard of care for DM includes glucocorticoids, immunosuppressants, and intravenous immunoglobulin (IVIg). Unfortunately, these medications are not uniformly effective and can lead to adverse events, particularly with chronic use, necessitating discontinuation of therapy. Therefore, a substantial unmet need exists for more tailored and efficacious therapies that target DM pathogenesis. Brepocitinib is an oral, once-daily, novel, and specific TYK2/JAK1 inhibitor. Brepocitinib's potent inhibition of TYK2 and JAK1 reduces the signalling of pro-inflammatory cytokines, including IFN-α/β, IL-12, IL-23, and IFNγ, that have been implicated in the pathogenesis of DM. Other JAK inhibitors have been used off-label in both case series and open-label clinical trials in patients with DM; and brepocitinib has demonstrated efficacy in phase 2 clinical trials of several other autoimmune diseases, including plaque psoriasis, psoriatic arthritis, Crohn's disease, hidradenitis suppurativa, and ulcerative colitis. Therefore, there is a strong scientific and clinical rationale for the utility and potential effectiveness of brepocitinib in the treatment of DM patients. Currently, the safety, tolerability, and efficacy of brepocitinib is being evaluated in the largest (n=225) double-blind placebo-controlled phase 3 trial in DM patients to date (VALOR - NCT0543726).
- MeSH
- dermatomyozitida * farmakoterapie diagnóza imunologie MeSH
- inhibitory proteinkinas * terapeutické užití škodlivé účinky MeSH
- Janus kinasa 1 * antagonisté a inhibitory MeSH
- kinasa TYK2 * antagonisté a inhibitory MeSH
- lidé MeSH
- signální transdukce účinky léků MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
OBJECTIVES: The phase 3 ProDERM study demonstrated intravenous immunoglobulin (IVIg) was safe and effective in patients with dermatomyositis (DM). This analysis assessed clinical and serological predictors of IVIg response in DM patients from ProDERM. METHODS: ProDERM was a prospective, randomized, placebo-controlled study of DM patients. For weeks 0-16, patients received 2.0 g/kg IVIg (Octagam, 10%) or placebo every 4 weeks. Eligible patients entered the open-label extension phase, where all received IVIg to week 40. Univariate and multivariate analyses examined associations between baseline variables and total improvement score (TIS), including myositis disease activity assessment tool (MDAAT; assessing different organ involvement), and myositis-specific and myositis-associated autoantibodies. RESULTS: Ninety-five patients were enrolled. Univariate analyses found no significant association between TIS at week 16 or 40 and age; sex; ethnicity; disease duration/activity; cutaneous, skeletal, gastrointestinal or muscle disease activity; or previous failed or concomitant medications. Multivariate analysis found patients with higher MDAAT cutaneous scores had a better chance of at least minimal TIS improvement. Higher MDAAT pulmonary scores were associated with a lower, but still considerable, chance of improvement. Patients with TIF1-γ antibodies had a better TIS response; however, after controlling for cutaneous disease activity, there was no significant association between antibody classification (including anti-TIF1-γ) and efficacy outcome. CONCLUSION: IVIg was effective in treating DM patients regardless of demographic features and autoantibody status (for most autoantibodies). Patients with higher cutaneous disease activity and/or anti-TIF1-γ responded best to IVIg, while pulmonary disease activity predicted a lower, but still effective, IVIg response, warranting further investigation. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02728752.
- MeSH
- autoprotilátky krev imunologie MeSH
- dermatomyozitida * farmakoterapie imunologie MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- imunologické faktory * terapeutické užití MeSH
- intravenózní imunoglobuliny * terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- prospektivní studie MeSH
- senioři MeSH
- stupeň závažnosti nemoci MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
OBJECTIVE: To study the trajectories of changes in damage over time and explore associations with autoantibody defined subgroups using a large international cohort of patients with idiopathic inflammatory myopathies (IIM). METHODS: Data from the MYONET registry, including patients who were tested for autoantibodies and had at least one assessment of damage using the Myositis Damage Index (MDI), were analyzed. Patients were sub-grouped according to their autoantibody profiles (myositis-specific, myositis-associated, or seronegative). The index date was defined as the time point for the first registered MDI assessment. The longitudinal trajectories of damage with autoantibody status as the main predictor were analyzed using linear mixed models. RESULTS: A total of 757 adult patients were included in this study. Each year of disease duration since diagnosis had an estimated MDI score increase of 0.16 units for the seronegative group (reference). Compared with the seronegative group as reference, patients with dermatomyositis-specific autoantibodies developed less damage per year of follow-up since diagnosis (average 0.08 less score, P = 0.04), whereas patients with anti-PM/Scl autoantibodies developed more damage per year of follow-up since diagnosis (average 0.28 higher score, P = 0.03) independent of sex and age at diagnosis. The seronegative subgroup and the immune-mediated necrotizing myopathy autoantibody subgroup had the strongest correlation between severity of muscle damage and HAQ-DI scores at five years of follow-up, rho=0.84, P < 0.001 and rho=0.72, P < 0.001, respectively. CONCLUSION: Our study is the first to describe patterns and trajectories of change in damage over time in relation to autoantibody defined subgroups in a large international multicenter cohort of patients with IIM. Patients with anti-PM/Scl scored a greater extent of damage, whereas patients with dermatomyositis-specific antibodies had less damage than seronegative patients. Severity in muscle damage had moderate to strong correlation with functional disability among the IMNM and seronegative subgroups with lower correlations for the other subgroups. These findings suggest that autoantibodies may be useful predictors of long-term damage.
- MeSH
- autoprotilátky * krev imunologie MeSH
- dermatomyozitida imunologie krev MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- longitudinální studie MeSH
- myozitida * imunologie krev MeSH
- progrese nemoci MeSH
- registrace * MeSH
- senioři MeSH
- stupeň závažnosti nemoci MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
OBJECTIVES: To compare clinical characteristics, including the frequency of cutaneous, extramuscular manifestations and malignancy, between adults with anti-synthetase syndrome (ASyS) and DM. METHODS: Using data regarding adults from the MYONET registry, a cohort of DM patients with anti-Mi2/-TIF1γ/-NXP2/-SAE/-MDA5 autoantibodies, and a cohort of ASyS patients with anti-tRNA synthetase autoantibodies (anti-Jo1/-PL7/-PL12/-OJ/-EJ/-Zo/-KS) were identified. Patients with DM sine dermatitis or with discordant dual autoantibody specificities were excluded. Sub-cohorts of patients with ASyS with or without skin involvement were defined based on presence of DM-type rashes (heliotrope rash, Gottron's papules/sign, violaceous rash, shawl sign, V-sign, erythroderma, and/or periorbital rash). RESULTS: In total 1054 patients were included (DM, n = 405; ASyS, n = 649). In the ASyS cohort, 31% (n = 203) had DM-type skin involvement (ASyS-DMskin). A higher frequency of extramuscular manifestations, including Mechanic's hands, Raynaud's phenomenon, arthritis, interstitial lung disease and cardiac involvement differentiated ASyS-DMskin from DM (all P < 0.001), whereas higher frequency of any of four DM-type rashes-heliotrope rash (n = 248, 61% vs n = 90, 44%), violaceous rash (n = 166, 41% vs n = 57, 9%), V-sign (n = 124, 31% vs n = 28, 4%), and shawl sign (n = 133, 33% vs n = 18, 3%)-differentiated DM from ASyS-DMskin (all P < 0.005). Cancer-associated myositis (CAM) was more frequent in DM (n = 67, 17%) compared with ASyS (n = 21, 3%) and ASyS-DMskin (n = 7, 3%) cohorts (both P < 0.001). CONCLUSION: DM-type rashes are frequent in patients with ASyS; however, distinct clinical manifestations differentiate these patients from classical DM. Skin involvement in ASyS does not necessitate increased malignancy surveillance. These findings will inform future ASyS classification criteria and patient management.
- MeSH
- aminoacyl-tRNA-synthetasy imunologie MeSH
- autoprotilátky * krev imunologie MeSH
- dermatomyozitida * imunologie komplikace MeSH
- dospělí MeSH
- exantém etiologie MeSH
- intersticiální plicní nemoci imunologie etiologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- myozitida * imunologie komplikace MeSH
- nádory komplikace MeSH
- registrace * MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
OBJECTIVES: To develop and validate the cut-offs in the Juvenile DermatoMyositis Activity Index (JDMAI) to distinguish the states of inactive disease (ID), low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA) in children with juvenile dermatomyositis (JDM). METHODS: For cut-off definition, data from 139 patients included in a randomised clinical trial were used. Among the six versions of the JDMAI, JDMA1 (score range 0-40) and JDMAI2 (score range 0-39) were selected. Optimal cut-offs were determined against external criteria by calculating different percentiles of score distribution and through receiver operating characteristic curve analysis. External criteria included the modified Pediatric Rheumatology International Trials Organization (PRINTO) criteria for clinically ID in JDM (for ID) and PRINTO levels of improvement in the clinical trial (for LDA and HDA). MDA cut-offs were set at the score interval between LDA and HDA cut-offs. Cut-off validation was conducted by assessing construct and discriminative ability in two cohorts including a total of 488 JDM patients. RESULTS: The calculated JDMAI1 cut-offs were ≤2.4 for ID, ≤6.6 for LDA, 6.7-11 for MDA and >11 for HDA. The calculated JDMAI2 cut-offs were ≤5.2 for ID, ≤8.5 for LDA, 8.6-11.3 for MDA and >11.3 for HDA. The cut-offs discriminated strongly among disease activity states defined subjectively by caring physicians and parents, parents' satisfaction or non-satisfaction with illness outcome, levels of pain, fatigue, physical functional impairment and physical well-being. CONCLUSIONS: Both JDMAI1 and JDMAI2 cut-offs revealed good metrologic properties in validation analyses and are, therefore, suited for application in clinical practice and research.
- MeSH
- dermatomyozitida * diagnóza MeSH
- dítě MeSH
- lékaři * MeSH
- lidé MeSH
- randomizované kontrolované studie jako téma MeSH
- revmatologie * MeSH
- ROC křivka MeSH
- stupeň závažnosti nemoci MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Dermatomyositis is an idiopathic inflammatory myopathy characterised by rashes and progressive muscle weakness. The recent ProDERM (Progress in DERMatomyositis) study is the first large randomised, placebo-controlled trial to establish the efficacy and safety of intravenous immunoglobulin (IVIg) in adult patients with dermatomyositis. Objectives of this analysis were to closely examine the safety and tolerability of IVIg in patients from the ProDERM study. METHODS: ProDERM was a double-blind, randomised, placebo-controlled, multicentre, phase 3 study. In the first period (weeks 0-16), adults with active dermatomyositis received 2.0 g/kg IVIg (Octagam 10%; Octapharma AG) or placebo every 4 weeks. In the open-label extension period (weeks 16-40), all patients received IVIg for 6 additional cycles; dose reduction (1.0 g/kg) was permitted if patients were stable. Treatment-emergent adverse events (TEAEs) were documented. RESULTS: The 95 patients enrolled were randomised to receive IVIg (N = 47) or placebo (N = 48) in the first period, with 5 switching from placebo to IVIg. Overall, 664 IVIg infusion cycles were administered. During the first period, 113 TEAEs were possibly/probably related to treatment in 30/52 patients (57.7%) receiving IVIg and 38 in 11 patients (22.9%) on placebo. Eight patients discontinued therapy due to IVIg-related TEAEs. Eight thromboembolic events (TEEs) occurred in six patients on IVIg; six in five patients were deemed possibly/probably related to IVIg. Patients with TEEs exhibited more baseline TEE risk factors than those without TEEs (2.4-15.2-fold higher). Lowering infusion rate reduced the rate of TEEs, and none occurred at the lower IVIg dose. No haemolytic transfusion reactions or deaths occurred. CONCLUSIONS: Results from this study demonstrate that IVIg has a favourable safety profile for treatment of adult dermatomyositis patients and provides evidence that will help to inform treatment choice for these patients. Dermatomyositis patients receiving high-dose IVIg should be monitored for TEEs, and a low rate of infusion should be used to minimise TEE risk, particularly in those with pre-existing risk factors. TRIAL REGISTRATION: ProDERM study (NCT02728752).
- MeSH
- dermatomyozitida * farmakoterapie MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- intravenózní imunoglobuliny škodlivé účinky MeSH
- intravenózní infuze MeSH
- lidé MeSH
- myozitida * chemicky indukované MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in paediatric and adult dermatomyositis, the complex diversity of complement C4 in IIM pathology was unknown. METHODS: We elucidated the gene copy number (GCN) variations of total C4, C4A and C4B, long and short genes in 1644 Caucasian patients with IIM, plus 3526 matched healthy controls using real-time PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion. RESULTS: The large study populations helped establish the distribution patterns of various C4 GCN groups. Low GCNs of C4T (C4T=2+3) and C4A deficiency (C4A=0+1) were strongly correlated with increased risk of IIM with OR equalled to 2.58 (2.28-2.91), p=5.0×10-53 for C4T, and 2.82 (2.48-3.21), p=7.0×10-57 for C4A deficiency. Contingency and regression analyses showed that among patients with C4A deficiency, the presence of HLA-DR3 became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% had HLA-DR3 with an OR of 11.02 (1.44-84.4). Intragroup analyses of patients with IIM for C4 protein levels and IIM-related autoantibodies showed that those with anti-Jo-1 or with anti-PM/Scl had significantly lower C4 plasma concentrations than those without these autoantibodies. CONCLUSIONS: C4A deficiency is relevant in dermatomyositis, HLA-DRB1*03 is important in IBM and both C4A deficiency and HLA-DRB1*03 contribute interactively to risk of polymyositis.
- MeSH
- autoprotilátky genetika MeSH
- dermatomyozitida * MeSH
- dítě MeSH
- dospělí MeSH
- genetická predispozice k nemoci MeSH
- HLA-DR3 antigen genetika MeSH
- HLA-DRB1 řetězec genetika MeSH
- komplement 4 MeSH
- komplement C4a genetika MeSH
- lidé MeSH
- myozitida * MeSH
- rizikové faktory MeSH
- variabilita počtu kopií segmentů DNA MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: To assess the role of the anti-TIF1γ auto-antibody (aAb) IgG2 isotype as a biomarker of cancer in anti-TIF1γ aAb-positive adult DM. METHODS: International multicentre retrospective study with the following inclusion criteria: (i) diagnosis of DM according to ENMC criteria; (ii) presence of anti-TIF1γ IgG aAb determined using an in-house addressable laser bead immunoassay (ALBIA) from cryopreserved serums sampled at time of DM diagnosis and (iii) available baseline characteristics and follow-up data until the occurrence of cancer and/or a minimum follow-up of 1 year for patients without known cancer at diagnosis. Detection and quantification of anti-TIF1γ IgG2 aAb was done using the in-house ALBIA. In addition, a recent ELISA commercial kit was used for anti-TIF1γ IgG aAb quantification. RESULTS: A total of 132 patients (mean age 55±15 years) of whom 72 (54.5%) had an associated cancer were analysed. The association between the presence of cancer and the presence of anti-TIF1γ IgG2 aAb was statistically significant (P = 0.026), with an OR of 2.26 (95% CI: 1.10, 4.76). Patients with cancer displayed significantly higher anti-TIF1γ IgG2 aAb ALBIA values with a median value of 1.15 AU/ml (IQR: 0.14-9.76) compared with 0.50 AU/ml (IQR: 0.14-1.46) for patients without cancer (P = 0.042). In addition, patients with cancer displayed significantly higher anti-TIF1γ IgG aAb ELISA values with a median value of 127.5 AU/ml (IQR: 81.5-139.6) compared with 93.0 AU/ml (IQR: 54.0-132.9) for patients without cancer (P = 0.004). CONCLUSION: These results suggest considering anti-TIF1γ IgG2 ALBIA and IgG ELISA values as biomarkers of cancer in anti-TIF1 γ aAb-positive adult DM.
- MeSH
- analýza mediace MeSH
- autoprotilátky MeSH
- biologické markery MeSH
- dermatomyozitida * MeSH
- dospělí MeSH
- imunoglobulin G MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory * komplikace MeSH
- retrospektivní studie MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVE: The ACR-EULAR Myositis Response Criteria (MRC) were developed as a composite measure using absolute percentage change in six core set measures (CSMs). We aimed to further validate the MRC by assessing the contribution of each CSM, frequency of strength vs extramuscular activity improvement, representation of patient-reported outcome measures (PROM), and frequency of CSM worsening. METHODS: Data from adult dermatomyositis/polymyositis patients in the rituximab (n = 147), etanercept (n = 14), and abatacept (n = 19) trials, and consensus patient profiles (n = 232) were evaluated. The Total Improvement Score (TIS), number of improving vs worsening CSMs, frequency of improvement with and without muscle-related CSMs, and contribution of PROM were evaluated by MRC category. Regression analysis was performed to assess contribution of each CSM to the MRC. RESULTS: Of 412 adults with dermatomyositis/polymyositis, there were 37%, 24%, 25%, and 14% with no, minimal, moderate, and major MRC improvement, respectively. The number of improving CSMs and absolute percentage change in all CSMs increased by improvement category. In minimal-moderate improvement, only physician-reported disease activity contributed significantly more than expected by MRC. Of patients with at least minimal improvement, 95% had improvement in muscle-related measures and a majority (84%) had improvement in PROM. Patients with minimal improvement had worsening in a median of 1 CSM, and most patients with moderate-major improvement had no worsening CSMs. Physician assessment of change generally agreed with MRC improvement categories. CONCLUSION: The ACR-EULAR MRC performs consistently across multiple studies, further supporting its use as an efficacy end point in future myositis therapeutic trials.
- MeSH
- dermatomyozitida * farmakoterapie MeSH
- dospělí MeSH
- konsensus MeSH
- lidé MeSH
- myozitida * farmakoterapie MeSH
- polymyozitida * farmakoterapie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Intramural MeSH
OBJECTIVES: The 2016 ACR-EULAR Response Criteria for JDM was developed as a composite measure with differential weights of six core set measures (CSMs) to calculate a Total Improvement Score (TIS). We assessed the contribution of each CSM, representation of muscle-related and patient-reported CSMs towards improvement, and frequency of CSM worsening across myositis response criteria (MRC) categories in validation of MRC. METHODS: Data from JDM patients in the Rituximab in Myositis trial (n = 48), PRINTO JDM trial (n = 139), and consensus patient profiles (n = 273) were included. Observed vs expected CSM contributions were compared using Sign test. Characteristics of MRC categories were compared by Wilcoxon tests with Bonferroni adjustment. Spearman correlation of changes in TIS and individual CSMs were examined. Agreement between physician-assessed change and MRC categories was evaluated by weighted Cohen's kappa. RESULTS: Of 457 JDM patients with IMACS CSMs and 380 with PRINTO CSMs, 9-13% had minimal, 19-23% had moderate and 41-50% had major improvement. The number of improved and absolute percentage change of CSMs increased by MRC improvement level. Patients with minimal improvement by MRC had a median of 0-1 CSM worsened, and those with moderate/major improvement had a median of zero worsening CSMs. Of patients improved by MRC, 94-95% had improvement in muscle strength and 93-95% had improvement in ≥1 patient-reported CSM. IMACS and PRINTO CSMs performed similarly. Physician-rated change and MRC improvement categories had moderate-to-substantial agreement (Kappa 0.5-0.7). CONCLUSION: The ACR-EULAR MRC perform consistently across multiple studies, supporting its further use as an efficacy end point in JDM trials.
